Abstract
To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN > or = 2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.
Highlights
To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer
For patients treated with cetuximab alone or in combination with chemotherapy, objective response rates were 16.7% (3 of 18) and 31.9% (22 of 69), median progression-free survival were 3.5 and 5.5 months, and median overall survival were 15 and 21 months, respectively
To test the hypothesis that increases of EGFR GCN in a limited subset of cells would be more predictive of response, we explored the diagnostic performance of the decision rule ‘‘the proportion of cells, having a GCN higher than a specific value r, being higher than some value s.’’ In other words, this rule allows to analyze the predictive value of specific increases of GCN within subsets of polysomic cells
Summary
To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. Novel strategies that target the epidermal growth factor receptor (EGFR) have led to the clinical development of a variety of agents, including small inhibitory molecules and monoclonal antibodies (mAb) Two such mAbs, panitumumab and cetuximab, are active in metastatic colorectal cancer, but only subgroups of patients respond to these agents (1 – 3) and reliable markers predictive of treatment benefit still need to be defined. Variations of gene copy numbers (GCN), either in terms of gains or losses, reflect the many different routes taken by individual tumors to disrupt/escape mechanisms governing normal cellular behavior These genomic aberrations have been successfully investigated by fluorescence in situ hybridization (FISH) in a number of malignancies. Despite the implications of these features for the global interpretation and the reproducibility of the assay in colorectal cancer, to our knowledge, no study far has addressed this critical point with respect to outcome prediction after anti-EGFR mAbs
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